Non-Peptidic inhibitors of human chymase. Synthesis, structure–activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones

Akahoshi, Fumihiko; Ashimori, Atsuyuki; Yoshimura, Takuya; Imada, Teruaki; Nakajima, Masahide; Mitsutomi, Naoko; Kuwahara, Susumu; Ohtsuka, Tatsuyuki; Fukaya, Chikara; Miyazaki, Mizuo; Nakamura, Norifumi

doi:10.1016/s0968-0896(00)00244-3

Cited by 12 publications

(5 citation statements)

References 38 publications

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“…Chymase could influence lung and airway function, even if not originating in the lung in light of recent evidence that chymase can circulate in an active, angiotensin II-generating form bound to a 2 -macroglobulin (106). In humans, clarification of suggested roles of chymase in asthma and other allergic conditions, scarring lung diseases, and pathologies affecting pleura and pulmonary vasculature must await testing of selective inhibitors, which have been developed using rational design strategies on several drug platforms, aided by the availability of high-quality, crystal-derived models of the human chymase active site (126)(127)(128)(129)(130)(131)(132).…”

Section: Chymasesmentioning

confidence: 99%

Mast Cell Peptidases

Trivedi¹,

Caughey²

2010

Am J Respir Cell Mol Biol

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Mast cells make and secrete an abundance of peptidases, which are stored in such large amounts in granules that they comprise a high fraction of all cellular protein. Perhaps no other immune cell is so generously endowed with peptidases. For many years after the main peptidases were first described, they were best known as markers of degranulation, for they are released locally in response to mast cell stimulation and can be distributed systemically and detected in blood. The principal peptidases are tryptases, chymases, carboxypeptidase A3, and dipeptidylpeptidase I (cathepsin C). Numerous studies suggest that these enzymes are important and even critical for host defense and homeostasis. Endogenous and allergen or pathogen-associated targets have been identified. Belying the narrow notion of peptidases as proinflammatory, several of the peptidases limit inflammation and toxicity of endogenous peptides and venoms. The peptidases are interdependent, so that absence or inactivity of one enzyme can alter levels and activity of others. Mammalian mast cell peptidases--chymases and tryptases especially--vary remarkably in number, expression, biophysical properties, and specificity, perhaps because they hyper-evolved under pressure from the very pathogens they help to repel. Tryptase and chymase involvement in some pathologies stimulated development of therapeutic inhibitors for use in asthma, lung fibrosis, pulmonary hypertension, ulcerative colitis, and cardiovascular diseases. While animal studies support the potential for mast cell peptidase inhibitors to mitigate certain diseases, other studies, as in mice lacking selected peptidases, predict roles in defense against bacteria and parasites and that systemic inactivation may impair host defense.

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Section: Chymasesmentioning

confidence: 99%

Mast Cell Peptidases

Trivedi¹,

Caughey²

2010

Am J Respir Cell Mol Biol

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“…Substituents at this position are thought to interact with the S 2 pocket of the enzyme. SAR study of 5-amino-6-oxo-1,6-dihydropyrimidine derivatives with a trifluoromethyl ketone group has indicated that an aromatic ring at this position is essential to maintain potent chymase-inhibitory activity and that the introduction of a substituent at the 3-position of the phenyl ring increases activity …”

Section: Resultsmentioning

confidence: 99%

“…SAR study of 5-amino-6-oxo-1,6dihydropyrimidine derivatives with a trifluoromethyl ketone group has indicated that an aromatic ring at this position is essential to maintain potent chymase-inhibitory activity and that the introduction of a substituent at the 3-position of the phenyl ring increases activity. 43 We therefore focused on 3-substituted phenyl groups. The nonsubstituted phenyl analogue 2n was found to be more potent (K i ) 5.57 nM) than compound 2g.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic α-Keto Heterocycles as Novel Inhibitors of Human Chymase

et al. 2001

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We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed structure-activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidinone ring revealed that 2r (Y-40079) had the most potent chymase-inhibitory activity (K(i) = 4.85 nM). This compound was also effective toward chymases of nonhuman origin and showed good selectivity for chymases over other proteases. Pharmacokinetic studies in rats indicated that 2r was absorbed slowly after oral administration and showed satisfactory bioavailability (BA) (T(max) = 6.0 +/- 2.3 h, BA = 19.3 +/- 6.6%, t(1/2) = 35.7 +/- 13.3 h). In conclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.

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“…On this basis, and in analogy to that proposed by Veale C.A. et al for HLE inhibitors (see herein-above) [ 118 ], Akahoshi F. and co-workers used the tripeptidic sequence Val–Pro–Phe as reference motif and synthesized a set of orally active pseudo-peptidyl t-FMKs with a pyrimidinone scaffold as isosteric replacement of the Val–Pro dipeptidic fragment at the P 3 -P 2 site [ 123 ]. The most relevant SAR insights of this series of chymase inhibitors are reported in Figure 16 , together with the K i values of the most potent and selective derivative ( K i = 50.6 nM), the reference peptidic analogue ( K i = 82.1 nM), and the compound which showed the best pharmacokinetic parameters after oral administration in rats ( K i = 305 nM).…”

Section: Peptidyl Tri-fluoromethyl Ketones (T-pfmks)mentioning

confidence: 99%

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

Citarella

Micale

2020

Molecules

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Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections.

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Non-Peptidic inhibitors of human chymase. Synthesis, structure–activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones

Cited by 12 publications

References 38 publications

Mast Cell Peptidases

Mast Cell Peptidases

Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic α-Keto Heterocycles as Novel Inhibitors of Human Chymase

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

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